Novel inhibitors of the luminal lineage transcription factor peroxisome proliferator-activated receptor gamma (PPARG) durably eradicate tumors in urothelial cancer (UC) animal models

Background: Small molecule targeting of cell lineage-defining transcription factors is a demonstrated and effective therapeutic strategy in oncology, exemplified by estrogen receptor (ER) agents luminal breast cancer. Two-thirds advanced UC classified as overexpression PPARG characteristic this molecular subtype. Currently, there poor understanding how recurrent missense mutations its obligate heterodimer retinoid X alpha (RXRA) impact function; previous tool compounds designed to inhibit have minimal phenotypic activity lines. Material Methods: The inhibitor FTX-6746 was evaluated lines including UMUC9 (PPARG amplification) HT1197 (RXRA-S427F hotspot mutation), which activate different genetic mechanisms. In vitro analyses included clonogenic growth assays assessment target gene modulation after treatment. vivo studies were performed NCG or Balb/C nude mice with oral administration at doses indicated below. Results: Our biochemical indicate that patient-derived RXRA bias an active conformation PPARG, mimicking agonist-bound state. Addressing the limitations compounds, we discovered novel inhibitors drive powerful repressive high specificity (>100X selective over PPARA/ PPARD). This results robust silencing cells (IC50 = 5 nM), inhibition preferentially observed activated signaling. Tumor regression two xenograft models well-tolerated no tumor regrowth upon cessation Treatment tumors 3, 10, 30 60 mg/kg twice daily resulted up 80% suppression tissue day 2 >100% 21. Similar efficacy treated FTX-6746, >45% 85–112% 42.Tabled 1ModelDose (mg/kg)Schedule%Tumor Growth Inhibition%Target Gene Suppression (D2)UMUC93BID*205916UMUC910BID*2070NDUMUC930BID*208373UMUC930BID*2110580UMUC960BID*21108NDHT119730BID*428546HT119760BID*4211259 Open table new tab Conclusions: These collective suggest factor small will be therapy for patients urothelial cancer harboring Conflict interest: Ownership: All authors are shareholders Flare Therapeutics.